April 2, 2010

Aliquots — research highlights from VUMC laboratories


Smad4 flips cancer switch

Defining the role of transforming growth factor-beta (TGF-β) in cancer has been difficult because of its fickle nature. In the early stages of cancer, TGF-β inhibits tumor growth but promotes tumor growth and metastasis in later disease stages. Smad proteins, intermediaries in the TGF-β signaling pathway, may play a role in TGF-β’s shifting functions.

Pran Datta, Ph.D., and colleagues have found that TGF-β promotes invasiveness and metastasis in colorectal cancer cell lines deficient in Smad4 (one member of the Smad family). However, in cell lines expressing Smad4, TGF-β acts as a tumor suppressor. In a mouse model of colorectal cancer metastasis, treatment with a TGF-β signaling inhibitor prevented metastasis to the liver and also regulated the expression of a number of tumor-associated proteins.

The results, reported in the March issue of Gastroenterology, suggest that loss of Smad4 in colorectal cancer might prompt the functional “shift” of TGF-β from tumor suppressor to tumor promoter – and that TGF-beta signaling inhibitors might hold promise as therapeutics for colorectal cancer.

Melissa Marino


Protein processing in aging eyes

Unique protein structures called “beaded filaments” are key elements in the determining the cytoskeletal architecture and optical properties of the lens of the eye. The filaments consist of two proteins – filensin and CP49. Mutations in the genes that encode them cause cataracts, although it is not known exactly how the mutations affect protein structure or function.

Wellcome Images

Wellcome Images

Kevin Schey, Ph.D., and colleagues studied normal processing of these proteins – called post-translational modifications – as the lens ages. In the March issue of Investigative Ophthalmology & Visual Science, they report two unusual modifications: N-acetylation and N-myristoylation of the new N- termini of filensin after the protein was truncated at two sites.

The study is the first comprehensive examination of post-translational modifications of beaded filament proteins in the lens, the researchers reported. Mapping this “proteolytic pathway” is important to understanding the role that the proteins play in health and disease.

Bill Snyder


Quenching the fires of inflammation

Macrophages are the among the body’s first responders – the inflammatory responses they unleash can stop the spread of infection and contain damage to tissues caused by trauma. Too much inflammation, however, can lead to septic shock and cause chronic disorders including arthritis, asthma and heart disease. Synthetic glucocorticoids like dexamethasone can suppress inflammation, but they often fail to put out the fire completely.

In the March 11 issue of the journal Blood, Sandip Bhattacharyya, Ph.D., and colleagues report the enzyme TAK1, a critical element in inflammatory cascades, also determines the macrophage’s response to glucocorticoids. Toll-like receptors (TLRs) are molecular sensors that recognize pathogen-associated molecular patterns. Direct activation of TAK1 is required for TLR-mediated, pro-inflammatory cytokine secretion in macrophages. In some inflammatory pathways, however, TAK1 activation is resistant to glucocorticoids. Understanding this differential response “promises to be an important avenue for future investigation,” the researchers report.

Bill Snyder


Signal for staph’s immune system dodge

Staphylococcus aureus – one of the most significant infectious threats to public health – expresses a range of “virulence factors” to combat the body’s defense systems. The signals that prompt staph to express these factors remain elusive.

Wellcome Images

Wellcome Images

One signal was proposed to be the toxicity of heme compounds, because S. aureus without a heme-detoxifying protein called HrtA expresses factors that block the recruitment of bacteria-gobbling neutrophils. In the March issue of PLoS Pathogens, Eric Skaar, Ph.D., and colleagues report that instead of heme toxicity triggering the immunomodulatory program, it appears that dysregulation of HrtA’s partner HrtB – a protein that forms pores in the bug’s membrane – actually sparks the anti-neutrophil response. Overexpression of HrtB in normal S. aureus or exposure of S. aureus to membrane pore-forming antimicrobial peptides induces a similar program.

The findings provide evidence that S. aureus senses membrane damage and expresses factors that help it evade immune-mediated clearance. Components of this program represent potential therapeutic targets.

Leigh MacMillan


We welcome suggestions for research to highlight in Aliquots. The items should be primary research articles (no reviews, editorials or commentaries) published within the last two months in a peer-reviewed journal. Please send the article citation (PDF if available) and any other feedback about the column to: aliquots@vanderbilt.edu.

Past Aliquots

June 22, 2012
June 8, 2012
May 11, 2012
April 27, 2012
April 13, 2012
March 30, 2012
March 16, 2012